Medical material and process for its production

ABSTRACT

A medical material comprising a shaped article made of a soft vinyl chloride resin composition, a layer formed on the shaped article and composed essentially of crosslinked gelatin having good bio-compatibility with a living body, and an intermediate bonding layer firmly bonding the crosslinked gelatin layer to the shaped article.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to a medical material such as a bloodtransportation tube and a process for its production. More particularly,the present invention relates to such a medical material made of a softvinyl chloride resin composition as the main constituent, which is madenot to elute a substance toxic to blood, body fluid or medicinal liquid,such as a pyrogenous substance, and a process for its production.

Discussion of the Background

As a material for a transportation tube used for the collection from thehuman body, transportation or injection into a human body, of a blood ormedicinal liquid in the medical fields such as blood collection, bloodtransfusion, fluid therapy or a blood circulation system for anartificial kidney, a composition composed essentially of a soft vinylchloride resin has been used. The soft vinyl chloride resin has highlevels of various properties required for the material of suchtransportation tubes, such as transparency, flexibility, resiliency,chemical resistance, high temperature properties and low temperatureproperties, and yet it is inexpensive. Therefore, it is suitable for useas a disposable article which is preferred also from the hygienic pointof view.

However, when the soft vinyl chloride resin is used for such purposes, aplasticizer, stabilizer or other resin additives incorporated in thesubstrate resin are likely to elute to the blood or liquid during itsuse. Further, it has been pointed out that when brought in contact withblood, the soft vinyl chloride resin is likely to lead to hemolysis orblood coagulation.

In order to cope with the above-mentioned difficulties, it has beenattempted to form a crosslinked gelatin layer on the inner surface ofthe tube made of the soft vinyl chloride resin, thereby to prevent theelution of the plasticizer, stabilizer or other resin additives to theblood or medicinal liquid and to solve the problems of hemolysis andblood coagulation at the same time.

SUMMARY OF THE INVENTION

Under these circumstances, it is an object of the present invention toprovide a medical material such as a tube or sheet made of the softvinyl chloride resin, which is made not to elute pyrogenous substancesto blood or medicinal liquid and which is free from impurities.

Another object of the present invention is to provide a bloodtransportation tube, whereby the above-mentioned difficulties aresubstantially reduced.

According to the first aspect, the present invention provides a medicalmaterial comprising a shaped article made of a soft vinyl chloride resincomposition, a layer formed on the shaped article and composedessentially of crosslinked gelatin having good bio-compatibility with aliving body, and an intermediate bonding layer firmly bonding thecrosslinked gelatin layer to the shaped article.

According to the second aspect, the present invention provides a processfor producing such a medical material, which comprises uniformly wettingthe surface of a shaped article made of a soft vinyl chloride resincomposition, with a gelatin solution to form a non-crosslinked gelatincoating layer in a wet state, contacting a solution of a crosslinkingagent to the coating layer to crosslink the non-crosslinked gelatincoating layer, removing any excessive solution of the crosslinking agentfrom the surface of the shaped article, and contacting the crosslinkedgelatin layer of the shaped article to pyrogen-free water at atemperature of from 50° to 80° C. for at least two hours for cleaning.

According to the third aspect, the present invention provides a bloodtransportation tube comprising an outer tubular layer of a soft vinylchloride resin composition, an inner tubular layer formed on the insideof the outer tubular layer and composed essentially of said crosslinkedgelatin, and an intermediate bonding layer firmly bonding the innertubular layer to the outer tubular layer.

According to the fourth aspect, the present invention provides a processfor producing such a blood transportation tube, which comprises:

a first step of filling a tube made of a soft vinyl chloride resincomposition, with a solution of a composition for forming a bondinglayer, to uniformly wet the inner surface of the tube with the solution,then removing most of the solution from the tube, and drying the layerof the solution uniformly remaining on the inner surface of the tube toform a bonding layer;

a second step of filling the tube with a gelatin solution to uniformlywet the surface of the bonding layer with the gelatin solution, thenremoving most of the gelatin solution from the tube to form anon-crosslinked gelatin layer in a wet state on the surface of thebonding layer, thereafter filling the tube with a solution of acrosslinking agent for a non-crosslinked gelatin layer, to crosslink thenon-crosslinked gelatin layer, and removing the solution of thecrosslinking agent from the tube;

a third step of filling the tube with a plasticizing solution for thecrosslinked gelatin layer, to have the plasticizing solution absorbed inthe crosslinked gelatin layer in a wet state; and

a fourth step of removing the plasticizing solution for the crosslinkedgelatin layer from the tube and drying the inside of the tube.

BRIEF DESCRIPTION OF THE DRAWINGS

In the accompanying drawings,

FIG. 1 is an enlarged cross-sectional view of a blood transportationtube according to the present invention.

FIG. 2 is a diagrammatic view of an apparatus used for a test for theelution of a plasticizer from the tube.

FIG. 3 is an enlarged sectional view of the sheet obtained in Example 7.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Now, the present invention will be described in detail with reference tothe preferred embodiments.

In the present invention, the vinyl chloride resin includes a polyvinylchloride and a copolymer of vinyl chloride with other compoundscopolymerizable therewith. As the compounds copolymerizable with vinylchloride, there may be mentioned ethylene, propylene, vinyl acetate,acrylic acid, an alkyl ester of acrylic acid, methacrylic acid, an alkylester of methacrylic acid, maleic acid, fumaric acid, itaconic acid,acrylonitrile or vinylidene chloride.

To soften the above vinyl chloride resin, from 30 to 60 parts by weightof a plasticizer is incorporated relative to 100 parts by weight of thesubstrate resin. As such a plasticizer, there may be mentioned aphthalic acid derivative such as di-2-octyl phthalate, di-2-ethylhexylphthalate or diisodecyl phthalate; an isophthalic acid derivative suchas diisooctyl isophthalate; an adipic acid derivative such as dioctyladipate; or other plasticizers such as tricresyl phosphate orepoxy-modified soybean oil.

In addition to the plasticizer, other resin additives such as a thermalstabilizer or a lubricant may also be incorporated into the above vinylchloride resin, in an amount of not more than 5 parts by weight relativeto 100 parts by weight of the substrate resin.

A usual blending and mixing technique, for instance, a method of using aribbon blender, a Bumbury's mixer, a super mixer or other blending ormixing machine, may be employed for blending the plasticizer and resinadditives to the substrate vinyl chloride resin.

The above-mentioned vinyl chloride resin is shaped into a tube or asheet preferably by extrusion molding. The tube preferably has across-section of a circular shape with the outer diameter of not morethan 10 mm, the inner diameter of at least 3 mm and a wall thickness ofabout 1 mm. The sheet preferably has a thickness of from 0.1 to 2 mm. Inthe following description, the invention will be described with respectto the tube as a representative of the shaped article.

Referring to the process for the production of a blood transportationtube, the first step comprises filling a tube made of a soft vinylchloride resin composition, with a solution of a composition for forminga bonding layer to uniformly wet the inner surface of the tube with thesolution, then discharging most of the solution from the tube, anddrying the layer of the solution uniformly remaining on the innersurface of the tube to form a bonding layer. The bonding layer thusformed in the first step, has a function of firmly bonding the innertubular layer composed mainly of crosslinked gelatin having goodbio-compatibility with a living body, to the outer tubular layer.

As the effective ingredient in the solution of the composition forforming the bonding layer, there may be mentioned a hydrophilicwater-insoluble material. Preferred is a polymer of a compound having ahydrophilic group, or a random copolymer or block copolymer of acompound having a hydrophilic group with another compoundcopolymerizable therewith. Particularly preferred is an acrylic resin.

An acrylic resin having the above properties is a polymer or copolymerof a monomer having a hydroxyl group. As the monomer having a hydroxylgroup, there may be mentioned a hydroxyalkyl (meth)acrylate such ashydroxy methacrylate, hydroxymethyl methacrylate, 2-hydroxyethylacrylate, 2-hydroxyethyl methacrylate, 2-hydroxyethylpropyl acrylate,2-hydroxypropyl methacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropylmethacrylate, 2-hydroxybutyl acrylate, 2-hydroxybutyl methacrylate,4-hydroxybutyl acrylate, 4-hydroxybutyl methacrylate, 2-hydroxypentylacrylate, 2-hydroxypentyl methacrylate, 6-hydroxyhexyl acrylate or6-hydroxyhexyl methacrylate; or an acrylic monomer such as methacrylicacid, acrylamide, methacrylamide, diacetone acrylamide, diacetonemethacrylamide, methylol acryloamide or methyl methacryloamide.

As the compounds copolymerizable with the above-mentioned hydroxylgroup-containing monomer, there may be mentioned acrylic acid, methylacrylate, methyl methacrylate, ethyl acrylate, ethyl methacrylate,propyl acrylate, propyl methacrylate, butyl acrylate, butylmethacrylate, pentyl acrylate, pentyl methacrylate, hexyl acrylate,hexyl methacrylate, heptyl acrylate, heptyl methacrylate, acrylonitrile,methacrylonitrile or vinyl acetate.

The solution of the composition for forming a bonding layer is asolution of the above polymer in a liquid medium (solution type) or adispersion of the polymer in a liquid medium (emulsion type). As theliquid medium, there may be employed water, toluene, benzene, ethylacetate, ethyl alcohol, isopropyl alcohol, n-hexyl alcohol, cyclohexanolor a mixture thereof. In the case of the emulsion type, it is preferredto stabilize the system by incorporating an emulsifier.

In the first step, the tube to constitute the outer tubular layer, isfilled with the solution of the composition for forming a bonding layer,to uniformly wet the inner surface of the tube with this solution. Then,most of the solution is discharged from the tube to permit the solutionto remain on the inner surface of the tube in a uniform thickness. Asthe liquid medium of the remaining solution is evaporated by drying, athin bonding layer is formed. If the bonding layer is too thin, it isdifficult to control the thickness uniformly over the entire surface,and such a thin layer will not properly function as a bonding layer. Onthe other hand, if the bonding layer is too thick, the flexibility ofthe bonding layer will be impaired, and the final product is likely tobe defective as the finally obtainable tube is susceptible to breakagewhen bent. The thickness of the bonding layer is preferably from 2 to 10μm, more preferably from 3 to 6 μm.

The thickness of the bonding layer may be controlled by properlyadjusting the concentration of the solution of the composition forforming the bonding layer. The concentration of the solution ispreferably from 0.01 to 2% by weight of the solid content. To dry thelayer of the solution uniformly remaining on the inner surface of thetube, it is preferred to place the tube in a heating furnace (oven)adjusted to a temperature of from 60° to 140° C., and supply dried airfrom one end of the tube. The temperature of the heating furnace mayproperly be adjusted depending upon the boiling point of the liquidmedium of the solution. However, if the temperature is lower than 60°C., it takes long time for drying and bacteria are likely to propagate,such being undesirable. On the other hand, if the temperature is higherthan 140° C., the outer tubular layer made of a soft vinyl chlorideresin is likely to be softened, colored or thermally decomposed, suchbeing undesirable. The air to be supplied to the tube is pressurized. Ifthe pressure is too small, the evaporated portion of the liquid mediumcan not be transported. On the other hand, if the pressure is too high,the bonding layer is likely to be partially transported to form a wavedsurface, such being undesirable. Therefore, the pressure of the air tobe supplied to the tube is preferably selected within a range of from0.01 to 2 kg/cm².

In the second step, the tube thus processed by the first step is filledwith a gelatin solution to uniformly wet the surface of the bondinglayer with the gelatin solution. Then, most of the gelatin solution isremoved from the tube to form a non-crosslinked gelatin coating layer ina wet state on the surface of the bonding layer. Then, this tube isfilled with a solution of a crosslinking agent for crosslinking thenon-crosslinked gelatin coating layer, to crosslink the non-crosslinkedgelatin layer.

The crosslinked gelatin layer has good biocompatibility with a livingbody, and has a function to prevent the elution of the plasticizer,stabilizer or other resin additives incorporated in the outer tubularlayer, to blood.

Gelatin is obtained by the hydrolysis of collagen to polypeptide chains,or by the further splitting of such isolated polypeptide chains, and hasa molecular weight of from 15,000 to 250,000.

As a solvent for gelatin, there may be mentioned water, methyl alcohol,ethyl alcohol, n-propyl alcohol, isopropyl alcohol, secondary propylalcohol, tertiary propyl alcohol, glycerol, propylene glycol or acetone.These solvents may be used alone or in combination as a mixture of twoor more different kinds.

For filling the tube with the gelatin solution, the gelatin solution iskept at a temperature high enough to avoid the solidification ofgelatin, preferably at a temperature of at least 30° C., morespecifically from 35° to 60° C. After uniformly wetting the surface ofthe bonding layer formed in the first step, with this gelatin solution,most of the gelatin solution is removed from the tube. Then, thetemperature of tube is lowered to a level of not higher than 30° C.,preferably not higher than 10° C., to solidify the gelatin in thegelatin solution formed on the surface of the bonding layer and to forma non-crosslinked gelatin coating layer in a wet state. The thickness ofthe non-crosslinked gelatin coating layer may be adjusted by theconcentration of the gelatin solution or by the temperature of thegelatin solution filled in the tube. Namely, the higher theconcentration or the lower the temperature, the thicker the gelatinlayer formed on the inner surface of the tube.

If the concentration of the gelatin solution is too high, the viscositytends to be too high even when the temperature of the gelatin solutionis raised, whereby it becomes difficult to obtain a non-crosslinkedgelatin coating layer in a wet state in a uniform thickness on thebonding layer, or the gelatin coating layer tends to be too thick. Ifthe gelatin coating layer is too thick, the non-crosslinked gelatincoating layer is susceptible to breakage when the tube is filled withthe solution of a crosslinking agent, and it is difficult to obtain ablood transportation tube of good quality. On the other hand, if theconcentration of the gelatin solution is too low, the non-crosslinkedgelatin coating layer tends to be too thin, whereby it becomes difficultto adequately control the elution of the plasticizer, stabilizer orother resin additives from the outer tubular layer made of a soft vinylchloride resin composition, to blood. Therefore, the concentration ofthe gelatin solution is preferably such that the gelatin content is from5 to 20% by weight, more preferably from 8 to 15% by weight.

The tube formed with such a non-crosslinked gelatin layer in a wetstate, is then filled with a solution of a crosslinking agent for thenon-crosslinked gelatin layer, to crosslink the gelatin layer. By thecrosslinking of the gelatin layer, the elution of the plasticizer,stabilizer or other resin additives from the outer tubular layer toblood is remarkably decreased.

The solution of the crosslinking agent for the gelatin layer is anaqueous solution of a crosslinking agent. As such a crosslinking agent,there may suitably be used an aldehyde, an isocyanate, an acid chloride,a sulfonyl chloride, a chloroformate, an epoxy or epichlorohydrin. Amongthem, an aldehyde such as formaldehyde, glutaric aldehyde or glyoxal, isparticularly preferred.

The concentration of the solution of the crosslinking agent ispreferably from 0.1 to 2% by weight of the crosslinking agent.

In order to crosslink the non-crosslinked gelatin layer in a wet state,the tube is filled with the solution of the crosslinking agent and iskept in the filled state at room temperature for from 30 minutes to afew hours. The crosslinking reaction takes place during this period,whereby the gelatin layer is modified. Thereafter, the solution of thecrosslinking agent is removed from the tube. For the purpose of removingany excessive crosslinking agent still remaining on the surface of thetube, it is preferred to pass pyrogen-free water through the tube.

In a preferred embodiment of the invention, the tube is, after theremoval of the solution of the crosslinking agent, filled withpyrogen-free water heated to a temperature of from 50° to 80° C. toclean the crosslinked gelatin layer. This cleaning is intended to washoff non-crosslinked gelatin in the crosslinked gelatin layer, anunreacted crosslinking agent and undesirable substances contained in thegelatin. In order to wash off these substances, it is possible to eithercontinuously supply warm water to the tube after the completion of theabove-mentioned step, or fill the tube with warm water and leave it tostand still for a predetermined period of time under warm condition, andthen discharge the water. From the economical point of view, the latteris preferred.

If the temperature of the cleaning water is less than 50° C., bacteriaare likely to propagate. On the other hand, if the temperature is higherthan 80° C., the tube is likely to undergo property changes or thecrosslinked gelatin layer is likely to peel off, such being undesirable.When the tube is filled with pyrogen-free water heated to a level offrom 50° to 80° C. and left to stand under warm condition, it ispreferred to leave the filled tube to stand still for at least 2 hours.After completion of leaving it to stand still, the warm water isdischarged from the tube, and it is preferred to wash the crosslinkedgelatin layer with fresh pyrogen-free water.

After completion of the cleaning of the crosslinked gelatin layer, thetube can be used as it is, for liquid therapy. However, the crosslinkedgelatin layer lacks in flexiblity. Therefore, it is preferred to conductaftertreatment to have a plasticizing substance absorbed so that thegelatin layer is plasticized.

Namely, in the third step, while the crosslinked gelatin layer on theinner surface of the tube after the removal of the solution of thecrosslinking agent, is still in a wet state, the tube is filled with aplasticizing solution for the crosslinked gelatin layer to have theplasticizing solution absorbed in the crosslinked gelatin layer.

The crosslinked gelatin layer is extremely brittle when dried, and assuch, can not follow the flexural properties of the outer layer made ofa soft vinyl chloride resin, and is likely to break even with a smalldeformation. Such brittleness of the crosslinked gelatin layer issubstantially reduced when the plasticizing solution is absorbed in thecrosslinked gelatin layer.

As the plasticizing solution for the crosslinked gelatin layer, anaqueous solution of glycerin is preferred. This plasticizing solution ispreferably an aqueous solution containing from 5 to 50% by weight, morepreferably from 20 to 40% by weight, of glycerin.

In order to plasticize the crosslinked gelatin layer, the tube is filledwith the plasticizing solution and is kept in the filled state at roomtemperature for from 1 to 30 minutes.

In the fourth step, the plasticizing solution is removed from the tubeafter the completion of the third step, and the inside of the tube isdried. The drying of the inner surface of the tube in this step may beconducted under the same conditions as those for drying the liquidmedium of the solution of the composition in the first step.

In the process of the present invention, water used is required to bepyrogen-free water, and the gelatin, crosslinking agent, glycerin, etc.used are required to be selected so that they do not contain substancestoxic to the human body.

When the medical material of the present invention is a tube, it isuseful as a liquid transportation tube for the collection from the humanbody, the transportation, or the injection into the human body, of bloodor medicinal liquid in the medical fields such as blood collection,blood transfusion, fluid therapy or a blood circulation system of anartificial kidney. When the shaped article is a sheet, it is used forthe preparation of a bag-like container.

The present invention provides the following remarkable effects, and itsindustrial value is extremely high.

(1) The medical material such as a blood transportation tube accordingto the present invention has a coating layer composed essentially ofcrosslinked gelatin having excellent bio-compatibility with a livingbody, and thus is highly wettable with blood or medicinal liquid,whereby adhesion of bubbles on the surface of the shaped article or atrouble of the flow rate change can be avoided.

(2) The medical material such as a blood transportation tube accordingto the present invention has a coating layer composed essentially ofcrosslinked gelatin, whereby blood or medicinal liquid is not brought indirect contact with the tube or sheet made of a soft vinyl chlorideresin, and the elution of the plasticizer, stabilizer or other resinadditives incorporated to the soft vinyl chloride resin, to the blood ormedicinal liquid, can be substantially decreased.

(3) When the crosslinked gelatin layer formed on the surface of the tubeor sheet is washed with pyrogen-free warm water according to the presentinvention, it is possible to obtain a medical material wherein thecrosslinked gelatin layer contains no substantial pyrogenous substancesor other undesirable substances.

Now, the present invention will be described with reference to Examples.However, it should be understood that the present invention is by nomeans restricted to these specific Examples.

EXAMPLE 1 First Step

A commercially available soft polyvinyl chloride tube for artificialdialysis having an outer diameter of 7 mm, an inner diameter of 5 mm anda length of 6 m, was used.

10 parts by weight of a one polymer type acrylic resin adhesive (OribainBPS-3233, manufactured by Toyo Ink K.K., solvent: ethyl acetate, solidcontent: 36.5% by weight) was diluted with 90 parts by weight of ethylacetate. To 10 parts by weight of this diluted liquid, 90 parts byweight of ethyl alcohol was added to obtain a solution of a compositionfor forming a bonding layer having an adhesive concentration of 1% byweight.

The solution of the above composition was filled in the above-mentionedtube to uniformly wet the inner surface of the tube with the solution,and then most of the solution was removed from the tube. The tube with acoating layer of the composition uniformly remained on the inner surfaceof the tube, is placed in a heating furnace adjusted to the temperatureof 80° C., and a compressed air of 0.4 kg/cm² was supplied from one endof the tube, and this operation was continued for 10 minutes.

On the inner surface of the tube thereby obtained, there was formed abonding layer having a thickness of about 4 μm.

The presence or absence of the remaining solvent, ethyl acetate, in thebonding layer was inspected by gas chromatography, whereby no ethylacetate was detected.

Second Step

12 parts by weight of gelatin (JIS special grade, manufactured byKabushiki Kaisha Nippi), 60 parts by weight of pyrogen-free water and 28parts by weight of ethyl alcohol were mixed, and the mixture was heatedto 60° C. to obtain a gelatin solution.

The gelatin solution maintained at 60° C. was filled in the tube aftercompletion of the first step, to uniformly wet the surface of thebonding layer of the tube with the gelatin solution, and then most ofthe gelatin solution was removed from the tube. Then, the tube wasplaced in a cooling chamber adjusted to a temperature of 5° C. to hardenthe gelatin, whereby a non-crosslinked gelatin layer having a thicknessof about 300 μm in a wet state was formed on the surface of the bondinglayer.

This tube was filled with an aqueous solution containing 0.5% by weightof glutaraldehyde, and left to stand in a warm chamber adjusted to atemperature of 50° C. for 30 minutes for a crosslinking reaction tocrosslink the non-crosslinked gelatin layer.

The solution of the crosslinking agent was discharged from the tube, andthen pyrogen-free water was continuously passed through the tube at aflow rate of 100 cc/min for 10 minutes to wash out excessive aldehyde.

Third Step

While the crosslinked gelatin layer after completion of the second stepwas still in a wet state, an aqueous solution containing 20% by weightof glycerin was filled in the tube, and the tube was left to stand undersuch a condition at room temperature for 10 minutes to have the glycerinabsorbed in the crosslinked gelatin layer. Then, the aqueous glycerinsolution was discharged from the tube.

Fourth Step

The tube after completion of the third step was placed in a heatingfurnace adjusted to a temperature of 80° C. Compressed air of 0.4 kg/cm²was supplied from one end of the tube, and this operation was continuedfor 10 minutes to dry the inside of the tube.

The tube thereby obtained had a crosslinked gelatin layer having athickness of about 30 μm, and had a cross-sectional structure as shownby the enlarged cross-sectional view in FIG. 1. In FIG. 1, referencenumeral 1 indicates the outer layer of the tube made of polyvinylchloride, numeral 2 indicates the bonding layer, and numeral 3 indicatesthe inner layer made of crosslinked gelatin.

The crosslinked gelatin layer was peeled off from the tube, and theconcentration of glycerin contained in the layer was measured and foundto be about 30% by weight.

Inspection of the Elution of the Plasticizer from the Tube

The tube obtained in Example 1 was set up as shown diagrammatically inFIG. 2, and a horse blood serum was circulated, whereby the amount ofthe elution of the plasticizer dioctyl phthalate was analyzed. In FIG.2, reference numeral 4 is a container for warm water, numeral 5 is warmwater maintained at a temperature of 40° C., numeral 6 is a containerfor a horse blood serum 7, numeral 8 is the tube, and numeral 9 is arotary pump. The horse blood serum was continuously circulated for 10hours through the tube having a length of 6 m, and then the amount ofelution of dioctyl phthalate was analyzed by gas chromatography, andfound to be 0.5 ppm.

COMPARATIVE EXAMPLE 1

By using the same type of a soft polyvinyl chloride tube as used inExample 1, a horse blood serum was circulated in the same manner asabove, whereby the amount of elution of dioctyl phthalate was analyzedand found to be 5.5 ppm.

EXAMPLE 2

A tube for fluid therapy was prepared in the same manner as in Example 1except that after the crosslinking of the gelatin layer, the tube wasfilled with pyrogen-free water heated to a temperature of 70° C. andleft to stand in that state in an atmosphere adjusted to a temperatureof 70° C. for 10 hours, and then the water was discharged from the tube,and the inside of the tube was washed with fresh pyrogen-free water bycontinuously passing the pyrogen-free water through the tube at a flowrate of 100 cc/min for 10 minutes.

The tube for fluid therapy thereby obtained had a crosslinked gelatinlayer having a thickness of about 30 μm, and had a cross-sectionalstructure as shown by the enlarged cross-sectional view in FIG. 1.

The crosslinked gelatin layer was peeled off from the tube, and theconcentration of glycerin contained in the layer was measured and foundto be about 30% by weight.

Evaluation Test for the Tube

The tube obtained in Example 2 was set up as shown diagrammatically inFIG. 2, and a physiological sodium chloride solution was circulated for5 hours through the tube having a length of 6 m. The solution after thecirculation was analyzed with respect to the following items. Theresults are shown in Table 1.

In this Example, referring to FIG. 2, reference numeral 4 is a containerfor warm water, numeral 5 is warm water at a temperature of 40° C.,numeral 6 is a container, numeral 7 is the physiological sodium chloridesolution, numeral 8 is the tube, and numeral 9 is a rotary pump.

(a) Ultraviolet Absorption Spectrum

In accordance with the testing method for the approval of a dialysistype artificial kidney, the absorbance of ultraviolet rays having a wavelength of from 220 to 350 nm was measured with respect to the testsolution with a thickness of 10 mm, as compared with a blank testsolution. If the absorbance is not higher than 0.1, the tube issatisfactory.

(b) Pyrogenous Substance

In accordance with a testing method for pyrogenous substance by thePharmacopeia of Japan, a test solution was tested as compared with ablank test solution, whereby a Limrous method (wherein a horseshoe-crabblood serum was employed) was used. The test results are evaluated bythe following standards.

(-): No pyrogenous substance was detected.

(+): Pyrogenous substance was detected.

(c): The amount of remaining glutaraldehyde

In accordance with a colorimetric test by means of a Nessler reagent

EXAMPLES 3 to 6 and COMPARATIVE EXAMPLES 2 to 4

Tubes were prepared in the same manner as in Example 2 except that theconditions for the washing of the inside of the tube with water werechanged as identified in Table 1.

With respect to the tubes thus obtained, evaluation tests were conductedin the same manner as in Example 2. The results are shown in Table 1.

EXAMPLE 7 Preliminary Step

To 100 parts by weight of polyvinyl chloride (P=1400), 45 parts byweight of dioctyl phthalate was blended, and the mixture wasextrusion-molded to obtain a sheet having a size of 50×50 cm and athickness of 0.2 mm.

On one side of this sheet, the same type of a one polymer type acrylicresin adhesive as used in Example 2 was coated by a gravure printingmethod. This sheet was placed in a heating furnace adjusted to atemperature of 80° C., and dried.

Step for Forming a Crosslinked Gelatin Layer

On the undercoating layer of the sheet thus formed, the same type of agelatin solution as used in Example 2 was coated by a knife coatingmethod to form a non-crosslinked gelatin layer having a thickness ofabout 300 μm in a wet state.

This sheet was dipped in the same type of an aqueous glutaraldehydesolution as used in Example 2 and left to stand for 30 minutes tocrosslink the non-crosslinked gelatin layer.

Washing of the Sheet

The crosslinked gelatin layer of the sheet thereby obtained was washedwith pyrogen-free water to roughly remove the excess solution of thecrosslinking agent, and then the sheet was dipped in pyrogen-free watermaintained at a temperature of 70° C. for 10 hours.

Then, the sheet was taken out of the dipping solution, and washed withfresh pyrogen-free water.

Step for Aftertreatment

While the crosslinked gelatin layer after the washing of the sheet wasstill in a wet state, this sheet was dipped in a 20% glycerin aqueoussolution to have the glycerin absorbed in the crosslinked gelatin layer.

The sheet taken out from the aqueous glycerin solution, was placed in anoven heated to a temperature of 80° C. and left to stand for 30 minutesto dry the surface of the sheet.

The sheet thereby obtained had a crosslinked gelatin layer having athickness of about 30 μm, and had a cross-sectional structure as shownby the enlarged cross-sectional view in FIG. 3.

In FIG. 3, reference numeral 11 is a polyvinyl chloride sheet, numeral12 is the undercoating layer, and numeral 13 is the crosslinked gelatinlayer.

Evaluation Tests of the Sheet

The sheet obtained in Example 7 was cut into a size so that the totalsurface area of the front and rear sides was 1200 cm², this sheet wasfurther cut into a size of 5 cm in length and 0.5 cm in width, thenwashed with pyrogen-free water and dried in room temperature. The samplesheet thereby obtained was placed in a glass container having a capacityof 300 ml, and 200 ml of a physiological sodium chloride solution wasaccurately added. After closing the container with a stopper, thecontainer was heated at 121° C. for 1 hour by means of an autoclavesterilizer, and then left to cool to room temperature. The solutionthereby obtained was used as a test solution.

With respect to this test solution, the tests (a), (b) and (c) asdisclosed in Example 2 were conducted. The results are shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________           Temperature of              Remaining                                         washing Immersed time                                                                         Ultra-violet                                                                        Pyrogenous                                                                          glutaraldehyde                             Examples                                                                             water (°C.)                                                                    (hrs)   spectrum                                                                            substance                                                                           (ppm)                                      __________________________________________________________________________    Example 2                                                                            70      10      0.03  (-)   0.1                                                                              or less                                 Example 3                                                                            50      10      0.08  (-)   0.4                                        Example 4                                                                            80      10      0.03  (-)   0.1                                                                              or less                                 Example 5                                                                            70       2      0.08  (-)   1.0                                        Example 6                                                                            70      20      0.03  (-)   0.1                                                                              or less                                 Example 7                                                                            70      10      0.03  (-)   0.1                                                                              or less                                 Comparative                                                                          40      10      0.13  (+)   0.5                                        Example 2                                                                     Comparative                                                                          90       10*.sup.1                                                                            0.03  (-)   0.1                                                                              or less                                 Example 3                                                                     Comparative                                                                          70      1       0.25  (+)   20                                         Example 4                                                                     __________________________________________________________________________     Note:                                                                         *.sup.1 Peeling of the crosslinked gelatin layer from the tube was            observed.                                                                

From Table 1, the following is evident.

(1) When the temperature of the washing water is from 50° to 80° C. andthe time for contact of the crosslinked gelatin layer with the washingwater is at least 2 hours, the pyrogenous substance contained in thecrosslinked gelatin layer and the amount of the remaining aldehyde, canbe reduced to a satisfactory level (Examples 2 to 7).

(2) Whereas, when the temperature of washing water is too low(Comparative Example 2) or the time for contact of the gelatin layerwith the washing water is too short (Comparative Example 4), the washingof the crosslinked gelatin layer tends to be inadequate, and it islikely that the pyrogenous substance is detected or unreacted aldehydeat an undesirable level is detected. Further, if the temperature ofwashing water is too high, it is likely that peeling of the crosslinkedgelatin layer takes place.

We claim:
 1. A medical article, comprising a shaped article made of asoft vinyl chloride resin composition, a layer formed on the shapedarticle and composed essentially of crosslinked gelatin having a goodbio-compatibility with a living body, and an intermediate bonding layerfirmly bonding the crosslinked gelatin layer to the shaped article. 2.The medical article of claim 1, wherein the said shaped article is atube.
 3. The medical article of claim 1, wherein the said shaped articleis a sheet.
 4. A blood transportation tube comprising an outer tubularlayer made of a soft vinyl chloride resin composition, an inner tubularlayer formed on the inside of the said outer tubular layer and beingcomposed essentially of crosslinked gelatin having a goodbio-compatibility with a living body, and an intermediate bonding layerfirmly bonding the said inner tubular layer to the said outer tubularlayer.
 5. The medical article of claim 1, wherein the said vinylchloride resin composition is polyvinyl chloride or a copolymer of vinylchloride with ethylene, propylene, vinyl acetate, acrylic acid, andalkyl ester of acrylic acid, methacrylic acid, and alkyl ester ofmethacrylic acid, maleic acid, fumaric acid, itaconic acid,acrylonitrile or vinylidene chloride.
 6. The blood transporation tube ofclaim 4, wherein the said soft vinyl chloride resin composition ispolyvinyl chloride or a copolymer of vinyl chloride with ehylene,propylene, vinyl acetate, acrylic acid, an alkyl ester of acrylic acid,methacrylic acid, and alkyl ester of methacrylic acid, maleic acid,fumaric acid, itaconic acid, acrylonitrile or vinylidene chloride. 7.The medical article of claim 1, wherein the said vinyl chloride resincontains from 30 to 60 parts by weight of plasticizer per 100 parts byweight of the substrate resin.
 8. The blood transporation tube of claim4, wherein the said vinyl chloride resin comprises 30 to 60 parts byweight of a plasticizer per 100 parts by weight of the substrate resin.9. The medical article of claim 7, wherein the said plasticizercomprises a phthalic acid derivative including di-2-octyl phthalate,di-2-ethyhexyl phthalate or diisodecyl phthalate; and isophthalic acidderivative including diisooctyl isophthalate; and adipic acid derivativeincluding dioctyl adipate; triceresyl phosphate; or an epoxy-modifiedsoybean oil.
 10. The blood transporation tube of claim 8, wherein thesaid plasticizer comprises a phthalic acid derivative includingdi-2-octyl phthalate, di-2-ethylhexyl phthalate or diisodecyl phthalate;an isophthalic acid derivative including diisooctyl isophthalate; andadipic acid derivative including dioctyl adipate; tricresyl phosphate;or an epoxy-modified soybean oil.
 11. The medical article of claim 1,wherein the said resin comprises a thermal stabilizer or a lubricant.12. The blood transporation tube of claim 4, wherein the said resincomprises a thermal stabilizer or a lubricant.
 13. The medical articleof claim 2, wherein the said tube has an outer diameter of no more than10 mm and an inner diameter of at least 3 mm.
 14. The medical article ofclaim 13, wherein the said sheet has a thickness of from 0.1 to 2 mm.15. The blood transportation tube of claim 4, wherein the said tube hasan outer diameter of not more than 10 mm and an inner diameter of atleast 3 mm.
 16. The medical article of claim 1, wherein the saidintermediate bonding layer comprises a hydrophilic water-insolublematerial.
 17. The blood transportation tube of claim 4, wherein the saidintermediate bonding layer comprises a hydrophilic water-insolublematerial.
 18. The medical article of claim 1, wherein the saidintermediate bonding layer is a polymer of a compound having anhydrophilic group, or a random copolymer of block copolymer of acompound having a hydrophilic group with another compoundcopolymerizable therewith.
 19. The blood transporation tube of claim 4,wherein the said intermediate bonding layer is a polymer of a compoundhaving a hydrophilic group, or a random copolymer or block copolymer ofa compound having a hydrophilic group with another compoundcopolymerizable therewith.
 20. The medical article of claim 1, whereinthe said intermediate bonding layer comprises an acrylic resin.
 21. Theblood transportation tube of claim 15, wherein the said intermediatebonding layer comprises an acrylic resin.
 22. The medical article ofclaim 1, wherein the said gelatin is obtained by the hydrolysis ofcollagen to polypeptide chains, or by the further splitting of suchisolated polypeptide chains, and wherein the said gelatin has amolecular weight of from 15,000 to 250,000.
 23. The blood transportationtube of claim 4, wherein the said gelatin is obtained by the hydrolysisof collagen to polypeptide chains, or by the further splitting of suchisolated polypeptide chains, and wherein the said gelatin has amolecular weight of from 15,000 to 250,000.